Patient preference for emicizumab versus prior factor therapy in people with haemophilia A: Results from the HAVEN 3 and HAVEN 4 studies.
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SUBMITTER: Parnes A
PROVIDER: S-EPMC9293412 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionSurgery in people with haemophilia and factor VIII inhibitors is typically managed with perioperative administration of haemostatic agents to prevent or control the occurrence of bleeding events. Practical experience of surgery in patients with inhibitors who are receiving treatment with emicizumab is growing; however, the novelty of the situation means that standardised guidelines are lacking with regard to the concomitant administration of haemostatic agents, including dose and laboratory monitoring.AimTo review approaches to haemostatic management during major and minor invasive procedures in patients with haemophilia A and inhibitors, and to provide recommendations for controlling bleeding events.MethodsA search was conducted, limited to the past 4 years (January 2016-April 2020), pertaining to published evidence of surgery for patients receiving emicizumab. Publications identified from the search were manually reviewed to determine studies and case reports relevant for inclusion.ResultsIdentified literature and practical experience of the authors were used to build a consensus of practical recommendations for the concomitant administration of haemostatic agents during the perioperative period for elective surgery in patients with inhibitors who are receiving emicizumab.ConclusionsThe current evidence base indicates that surgery can be successfully performed in patients with inhibitors who are receiving emicizumab and that bypassing agents can be used concomitantly. Data from prospective studies are required to further support recommendations for haemostatic management of surgery in patients receiving emicizumab.
| S-EPMC8359827 | biostudies-literature
Project description:IntroductionEmicizumab is a subcutaneously (SC) administered prophylactic agent for persons with haemophilia A (PwHA). As part of its clinical development, a new instrument was required to measure treatment satisfaction.AimDescribe development of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection (SQ-ISHI) and its subsequent testing with HAVEN 3 study participants to measure patient satisfaction with emicizumab.MethodsTo develop the SQ-ISHI, we conducted four rounds of in-person interviews at five qualitative research facilities. Participants aged ≥12 years with moderate or severe haemophilia A, receiving intravenous factor VIII (FVIII) prophylaxis, provided feedback to optimize content understanding, ease of completion and item relevance. The final SQ-ISHI was completed by HAVEN 3 participants who previously received FVIII prophylaxis; baseline scores were compared with those at Week 21 or 25 of emicizumab prophylaxis.ResultsSixty-three HAVEN 3 participants were eligible to complete the questionnaire and rate their satisfaction on a scale of 0 ('not at all satisfied') to 10 ('extremely satisfied'). Mean 'overall satisfaction' with previous FVIII prophylaxis at baseline was 6.9 (95% confidence interval [CI]: 6.2 to 7.7) increasing to 8.8 (95% CI: 8.4 to 9.3) at follow-up (Week 21/25 of treatment with emicizumab). The greatest improvement was observed in satisfaction with treatment half-life (mean score at baseline: 5.8 [95% CI: 4.9 to 6.6] vs 8.6 [95% CI: 8.0 to 9.2] at follow-up).ConclusionThese results demonstrate that emicizumab prophylaxis leads to greater treatment satisfaction compared with FVIII prophylaxis, reflecting in part the low treatment burden of emicizumab associated with its infrequent, SC administration.
| S-EPMC8048849 | biostudies-literature
Project description:IntroductionEmicizumab is a humanised, bispecific monoclonal antibody mimicking the cofactor function of activated factor (F)VIII. It is indicated for routine prophylaxis of bleeding episodes in persons with haemophilia A (PwHA) with/without FVIII inhibitors.AimTo evaluate the development of anti-emicizumab antibodies and their impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy and safety in PwHA.MethodsData from seven completed or ongoing phase 3 studies were pooled. The assessment of the immunogenicity profile of emicizumab included anti-drug antibody (ADA) measurement and the association of ADAs with PK, PD, bleeding events, and adverse events.ResultsOf 668 PwHA evaluable for immunogenicity analysis, 34 (5.1%) developed ADAs after exposure to emicizumab. ADAs were transient in 14/34 PwHA (41.2%). ADAs were neutralising in vitro in 18/34 PwHA (52.9%) and associated with decreased emicizumab concentration in 4/668 evaluable PwHA (.6%); of those, one (.1%) discontinued emicizumab due to loss of efficacy. ADAs without decreased exposure did not impact emicizumab efficacy. The proportion of PwHA who had injection-site reactions (ISRs) was higher in ADA-positive PwHA (29.4% vs. 20.8%); however, the safety profile was similar between ADA-positive and ADA-negative PwHA, overall. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive participants.ConclusionThe immunogenicity risk of emicizumab in phase 3 studies was low. ADAs, including in vitro neutralising ADAs, were not associated with a change in safety profile. Routine surveillance is, therefore, not warranted; however, in cases where a loss and/or waning of efficacy are observed, prompt evaluation by a healthcare provider should be sought.
| S-EPMC9292930 | biostudies-literature
Project description:Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.
| S-EPMC8065240 | biostudies-literature
Project description:Objectives: A factor contributing to the value of patient preference studies is patient centricity. This study aimed to explore how patients want to be involved in the design and conduct of patient preference studies. In addition, we investigated patients' expectations regarding the communication of study results back to patients. Methods: Semi-structured interviews were conducted with patient representatives within three different disease areas: rheumatic diseases, cancer, and neuromuscular disorders. For each disease area, interviews were conducted with interviewees from Belgium, the Netherlands and the United Kingdom. Interviews followed a predefined interview guide covering topics relating to timing, level, and requirements for patient involvement in patient preference studies, as well as communication of results. Interviews were audio-recorded, transcribed and analyzed using framework analysis in NVivo 12. Results: A total of 14 interviews were conducted. Some interviewees believed that patients should be involved in all steps of a patient preference study. Patient involvement seemed most valuable during the design phase to support defining research questions and instrument design. During analysis, patients can be involved for optimal interpretation of results. Most interviewees mentioned that patient involvement should be on the level of advice or collaboration, not control. Interviewees expressed requirements for patient involvement relating to the knowledge of the involved patient, time investment, compensation and other incentives. Regarding communication of results, most interviewees wished to receive a brief and lay summary of the results, followed by a detailed explanation of both individual and average results accompanied by visuals. Conclusions: Patient involvement in patient preference studies could increase question comprehension by study participants and ensure correct interpretation of results by researchers. Patients want to be involved as advisors or collaborators, and considering their personal situation as well as establishing agreements on roles, time involvement and compensation early on will result in a most optimal partnership.
| S-EPMC7100374 | biostudies-literature
Project description:Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.
| S-EPMC7895541 | biostudies-literature
Project description:IntroductionSurgery is frequently required in persons with haemophilia A (PwHA). Emicizumab, a bispecific, humanized monoclonal antibody, bridges activated factor (F) IX and FX. Management of patients undergoing surgery while receiving emicizumab is of clinical interest due to paucity of data.AimReview real-world experience of PwHA with/without FVIII inhibitors who required surgery while receiving emicizumab prophylaxis.MethodsData regarding peri-operative management, including type of surgery, haemostatic agent use and bleeding complications, were collected for PwHA receiving emicizumab undergoing surgery between 25/10/18 and 31/12/19 at the Indiana Hemophilia and Thrombosis Center. Analyses were exploratory and descriptive.ResultsTwenty minor and five major surgeries were performed in 17 and five patients, respectively. Overall, 9/20 minor surgeries were planned to occur with emicizumab as the sole haemostatic agent; of these, four required additional coagulation factor (2 due to haematomas following port removals, 1 due to oozing at port removal site, 1 due to bleeding following squamous cell carcinoma removal). Three of the 11 minor surgeries with planned additional coagulation factor resulted in non-major bleeds; all were safely managed with additional coagulation factor. All five major surgeries were planned with additional haemostatic agents; there was 1 bleed in a patient undergoing elbow synovectomy with nerve transposition, likely triggered by physical/occupational therapy. There were no major bleeds, thrombotic events or deaths.ConclusionsAdditional haemostatic agent use is safe in PwHA undergoing surgery while receiving emicizumab. Additional data are needed to determine the optimal dosing/length of treatment of additional haemostatic agents to lower bleeding risk.
| S-EPMC7898816 | biostudies-literature
Project description:An important factor affecting preference formation is the context in which that preference decision takes place. The current research examined whether one's preference formed for a previously presented stimulus influences the processing of a subsequent preference decision, henceforth referred to as the preference sequence effect. Using a novel sequential rating/judgment paradigm, the present study demonstrated the presence of a preference sequence effect using artistic photographs and face stimuli: A neutral stimulus was preferred more following a preferable stimulus than a less preferable stimulus. Furthermore, a similar trend was found even when the potential influence of response bias was controlled. These results suggest that an assimilative sequential effect exists even when sequential judgments are made solely based on one's subjective feeling; preference formed for a preceding stimulus modulates preference for a subsequent stimulus. This implies the need for a consideration of trial sequence as a factor creating a psychological context affecting the subsequent preference decisions.
| S-EPMC5560581 | biostudies-literature
Project description:ObjectivesThe aim of the Patient preferences to Assess Value IN Gene therapies (PAVING) study was to investigate trade-offs that adult Belgian people with haemophilia (PWH) A and B are willing to make when choosing between prophylactic factor replacement therapy (PFRT) and gene therapy.MethodsThe threshold technique was used to quantify the minimum acceptable benefit (MAB) of a switch from PFRT to gene therapy in terms of 'Annual bleeding rate' (ABR), 'Chance to stop prophylaxis' (STOP), and 'Quality of life' (QOL). The design was supported by stakeholder involvement and included an educational tool on gene therapy. Threshold intervals were analysed using interval regression models in Stata 16.ResultsA total of 117 PWH completed the survey. Mean thresholds were identified for all benefits, but substantial preference heterogeneity was observed; especially for the STOP thresholds, where the distribution of preferences was bimodal. Time spent on the educational tool and residence were found to impact MAB thresholds. The most accepted (88% of PWH) gene therapy profile investigated in this study comprised of zero bleeds per year (vs. six for PFRT), 90% chance to stop prophylaxis, no impact on QoL, and 10 years of follow-up on side effects (vs. 30 for PFRT).ConclusionsResults from this study proved the value of educating patients on novel treatments. Moreover, preference heterogeneity for novel treatments was confirmed in this study. In gene therapy decision-making, preference heterogeneity and the impact of patient education on acceptance should be considered.
| S-EPMC9293173 | biostudies-literature
Project description:People with haemophilia (PWH) experience acute pain during joint bleeds and might develop chronic pain due to joint degeneration. However, there is a lack of standardized measures to comprehensively assess pain in PWH. This study aimed to develop a multidimensional questionnaire for haemophilia-related pain, the Multidimensional Haemophilia Pain Questionnaire (MHPQ), and to present initial validation data among adults.The questionnaire distinguishes between acute/chronic pain and queries about pain locations, duration, frequency, triggering factors, intensity, interference, strategies, specialists for pain management and satisfaction with treatment. An initial version was tested with 16 patients to ensure item comprehensibility and face validity. The final version was answered by 104 adults, with 82 (78.8%) reporting haemophilia-related pain in the previous year (mean age = 43.17; SD = 13.00). The non-response analysis revealed good item acceptability. Exploratory and confirmatory factor analysis (EFA/CFA), reliability (internal consistency, test-retest, inter-item and item-total correlations) and convergent validity were analysed for the intensity and interference dimensions of the questionnaire. A combined EFA with these two constructs supported a 2-factor structure distinguishing intensity (? = 0.88) from interference items (? = 0.91). CFA was tested for the interference dimension, demonstrating suitability for this sample. Item-total correlations were >0.30 on both dimensions and most inter-item correlations were <0.70. Test-retest reliability (n = 42) was good for intensity (r = 0.88) and interference (r = 0.73), and convergent validity was confirmed for most hypotheses (r>0.30).This questionnaire is a comprehensible tool, achieving a thorough assessment of relevant pain dimensions. The MHPQ can help guide treatment recommendations by highlighting relevant topics and contributing to more effective, integrated treatments.
| S-EPMC6261605 | biostudies-literature